Recommendations for measuring HIV reservoir size in cure-directed clinical trials

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Abstract

Therapeutic strategies are being clinically tested either to eradicate the latent HIV reservoir or to achieve virologic control in the absence of antiretroviral therapy (ART). Attaining this goal will require a consensus on how best to measure the levels of persistently-infected cells with the potential to cause viral rebound upon ART cessation to assess the results of cure-directed strategies in vivo . Current measurements assess different aspects of the HIV provirus and its functionality, and produce divergent results. Here, we provide the collective insight and position from the BEAT-HIV Martin Delaney Collaboratory on which viral measurements to prioritize in HIV cure-directed clinical trials.

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Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection.

Tae-Wook Chun, Lucy Carruth, Diana Finzi … (1997)

The capacity of HIV-1 to establish latent infection of CD4+ T cells may allow viral persistence despite immune responses and antiretroviral therapy. Measurements of infectious virus and viral RNA in plasma and of infectious virus, viral DNA and viral messenger RNA species in infected cells all suggest that HIV-1 replication continues throughout the course of infection. Uncertainty remains over what fraction of CD4+ T cells are infected and whether there are latent reservoirs for the virus. We show here that during the asymptomatic phase of infection there is an extremely low total body load of latently infected resting CD4+ T cells with replication-competent integrated provirus (<10(7) cells). The most prevalent form of HIV-1 DNA in resting and activated CD4+ T cells is a full-length, linear, unintegrated form that is not replication competent. The infection progresses even though at any given time in the lymphoid tissues integrated HIV-1 DNA is present in only a minute fraction of the susceptible populations, including resting and activated CD4+ T cells and macrophages.

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A novel quantitative approach for measuring the reservoir of latent HIV-1 proviruses

Katherine M. Bruner, Zheng Wang, Francesco R. Simonetti … (2019)

A stable latent reservoir for HIV-1 in resting CD4+ T-cells precludes cure 1–3 . Curative strategies targeting the reservoir are being tested 4,5 and require accurate, scalable reservoir assays. The reservoir was defined with quantitative viral outgrowth assays (QVOAs) for cells releasing infectious virus following one round of T-cell activation 1 . However, QVOAs and newer assays for cells producing viral RNA after activation 6 may underestimate reservoir size because one round of activation does not induce all proviruses 7 . Many studies rely on simple PCR-based assays to detect proviral DNA regardless of transcriptional status, but the clinical relevance of these assays is unclear, as the vast majority proviruses are defective 7–9 . We describe a novel approach that separately quantifies intact and defective proviruses and show that the dynamics of cells carrying intact and defective proviruses are different in vitro and in vivo, a finding with implications for targeting the intact proviruses that are a barrier to cure.